IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system
J. Clin. Invest. Shoji Sanada, et al. 117:1538 doi:10.1172/JCI30634 [Go to this article.]

Figure 2
IL-33 blocks prohypertrophic stimuli in cardiomyocytes and sST2 inhibits IL-33. (A) IL-33 demonstrated a nonsignificant trend toward stimulating hypertrophy, but IL-33 blocked angiotensin II– and phenylephrine-induced (Phe) leucine uptake in a dose-dependent manner. (B) sST2 dose-dependently reversed the antihypertrophic effect of IL-33 under angiotensin II and phenylephrine. (C) Anti-ST2L monoclonal antibody, which blocks membrane-bound ST2L receptor–binding activity, blocked the antihypertrophic effect of IL-33, unlike control IgG. (D) Leucine uptake was not affected by sST2 compared with either baseline or control protein IL-1R–related protein 2 (IL-1Rrp2), but further enhanced hypertrophy under angiotensin II and phenylephrine. Data are from 3–5 sets of experiments. (E) Quantitative analysis of in vitro cell size measurements of cardiomyocytes was consistent with leucine incorporation assays (n = 200 each). *P < 0.05 versus baseline; ^#P < 0.05. (F) Induced secretion of both sST2 and IL-33 can reduce free IL-33. Cardiac fibroblasts were treated with indicated doses of PMA for 24 hours to induce sST2 and IL-33. In the top blots, conditioned media (20 μl) were analyzed by Western analysis. PMA dose-dependently increased secretion of both IL-33 and sST2. Below, media were preincubated in the presence or absence of 20 μg sST2-Fc protein and then incubated with presaturated beads for 2 hours. Samples preincubated with sST2-Fc had little IL-33, indicating that preincubation with sST2-Fc removed free IL-33. PMA dose-dependently decreased free IL-33 despite an increase in overall IL-33; these data suggest that induced sST2 can function as a decoy receptor, decreasing free IL-33.